Serotonin has a muddling effect on the sensation of pain and itch, whereby, as serotonin spreads from brain to spinal cord, pain-sensing neurons instead influence itch intensity.
Scientists know from previous studies that a mild amount of pain in the skin is caused by scratching, which temporarily interferes with the itching sensation. This interference happens because, while scratching, nerve cells in the spinal cord carry pain signals to the brain instead of itch signals.
"The problem is that when the brain gets those pain signals, it responds by producing the neurotransmitter serotonin to help control that pain," says senior investigator Dr. Zhou-Feng Chen, PhD, director of Washington University's Center for the Study of Itch.
Dr. Chen and team found that serotonin has a muddling effect on the sensation of pain and itch, whereby, as serotonin spreads from brain to spinal cord, pain-sensing neurons instead influence itch intensity.
Based on our own experiences of chronic eczema, Medical News Today asked Dr. Chen if the team found any evidence that serotonin drove the itch-scratch cycle by providing a "reward" sensation when we scratch.
"In chronic itch condition, as you experienced, you probably don't get much reward/pleasure out of scratching, because the goal of scratching is to create pain to inhibit itching," replied Dr. Chen. "So in other words, you are forced to choose the lesser of two evils, because pain and itch are antagonistic."
"Incessant scratching is not due to additive sensation, it is because your scratching does not work. The reason is that, at least from our studies in mice, when you scratch to create pain, the brain in response begins to produce more serotonin to inhibit pain (the brain does not want to have pain in your body). What we found is that while serotonin inhibits itch, it also can activate the itch receptor and make more itching."
"Now the more itching you feel, the more pain you would like to create to counteract it," he explains. "The result is more itching..."
The researchers bred mice that lacked the genes necessary for serotonin production. When the serotonin-free mice were injected with a substance that would normally cause itching, the researchers found that the mice did not scratch as much as a control group of mice with the serotonin-producing genes.
Next, the mice that lacked the serotonin genes were injected with serotonin. The injected serotonin caused the mice to scratch in a manner that was consistent with the control group.
The team considered different approaches that might be useful in minimizing the itching sensation. They ruled out suppressing serotonin as - although this made the mice less sensitive to itching - serotonin is too valuable a chemical in the body.
Growth, aging, bone metabolism, mood and pain are all regulated by serotonin, so blocking this neurotransmitter would have consequences throughout the body. Instead, the team focused their attention on disrupting communication between serotonin and the nerve cells in the spinal cord that relay the itching impulse from brain to skin.
Serotonin activates GRPR neurons via the 5HT1A receptor
Dr. Chen and colleagues worked to isolate the receptor used by serotonin to activate these cells - called GRPR neurons. They achieved this by stimulating itching in the mice using the injected substance and then systematically activated different combinations of serotonin receptors on GRPR neurons.
In the study, mice that lacked serotonin-producing genes were injected with serotonin, which caused the mice to scratch more.
Eventually, this process revealed that the receptor 5HT1A activated the itch GRPR neurons in the spinal cord. To establish that 5HT1A was the correct receptor, the team administered a compound to block this receptor in mice, which resulted in the mice scratching much less.
As the team decided against blocking serotonin as a therapeutic option because of the widespread consequences its inhibition would have for the body, we asked Dr. Chen what consequences blocking 5HT1A might have.
"5HT1A is widely expressed in the brain, yes, blocking it may have adverse effects," he answered. "This will be found out with clinical trials as to whether adverse effects are tolerable."
However, Dr. Chen suggests that, when itch is not present, "5HT1A in other brain areas may not be very active," while in a chronic itching situation, 5HT1A activity may be "strongest in the spinal cord, so blocking its activity may have the benefit you need."
Based on the team's findings, Dr. Chen identifies the itch-pain cycle as happening in this order:
- First, scratching causes a sensation of pain
- Then the body makes more serotonin to control the pain
- As well as inhibiting pain, the serotonin activates the GRPR neurons via the 5HT1A receptors
- The activated GRPR neurons then make the itching sensation worse.
Next, the team will continue to work toward better understanding the molecular and cellular mechanisms involved in this cycle.